Folic acid and its related compounds are carriers of one-carbon (C1) units in a living body derived from formic acid or formaldehyde, acting as a coenzyme in various enzymatic reactions such as those in biosynthesis of nucleic acid, in metabolism of amino acids and peptides and in generation of methane. Particularly for metabolism or transfer reaction of C1 units in biosynthesis of nucleic acid, i.e. the purine synthetic pathway and the thymidine synthetic pathway, folic acid and its related compounds are essential. Usually, folic acid is efficiently stored intracellularly as oligoglutamates by glutamylation with folylpolyglutamyl synthase after being transformed into tetrahydrofolic acid being an activated coenzyme by reduction in two steps. This tetrahydrofolic acid and its oligoglutamates display biological activity as coenzyme in various enzymatic reactions in the state of combination with C1 units.
On the other hand, Amethopterin (methotrexate:MTX) and its related compounds are known as drugs to inhibit the reduction from dihydrofolic acid into tetrahydrofolic acid by coupling strongly with the dominant enzyme (dihydrofolate reductase) in this reduction. These drugs have been developed as antitumor drugs because they may disturb the DNA synthesis and consequently cause cell death, and are used clinically. Further, antifolates, having an action mechanism different from inhibition of dihydrofolate reductase, i.e. a tetrahydroaminopterin antitumor agent (5,10-dideaza-5,6,7,8-tetrahydroaminopterin: DDATHF), whose main action mechanism consists in inhibition of glycinamide ribonucleotide transformylase concerned in the initial stage of purine biosynthesis [Journal of Medicinal Chemistry, 28, 194 (1985)], and a quinazoline antitumor agent (2-desamino-2-methyl-10-propargyl-5,8-dideazafolate: DMPDDF), whose main action mechanism consists in inhibition of thymidylate synthase concerned in transformation of deoxyuridin monophosphate to deoxythimidine monophosphate [British Journal of Cancer 58, 241 (1988)], and their oligoglutamates [Journal of Medicinal Chemistry, 29, 1754 (1986) and 31, 181 (1988)] have been reported. However, their oligoglutamates have as a condensed heterocyclic moiety a condensed ring formed with two 6-membered rings but do not have a condensed ring formed with a 5-membered ring and 6-membered ring.
And, recently, it has been reported that, besides these antifolates and oligoglutamates having a condensed ring formed with a 6-membered ring and a 6-membered ring, compounds having a condensed ring formed with a 6-membered ring and a 5-membered ring, i.e. a pyrrolo[2,3-d] pyrimidine skeleton, have also excellent anti-tumor activity. For example, EP-A-334636 describes a compound of the formula: ##STR2## wherein a ring A is a pyrrole or pyrroline ring, X is an amino group or a hydroxyl group, Y is a hydrogen atom, an amino group or a hydroxyl group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl groups, --COOR.sup.l and --COOR.sup.2 are independently carboxyl group which may be esterified and n is an integer of 2 to 4, and R may be different in each of the n repeating units, and salts thereof have excellent antitumor effects, and can be used as antitumor agents in mammals, EP-A-400562 describes a compound of the formula: ##STR3## wherein a ring A is a pyrrole ring which may be hydrogenated, X is an amino, hydroxyl or mercapto group, Y is a hydrogen atom or a hydroxyl group, R.sup.1, R.sup.2, R.sup.4 and R.sup.5 may be the same or different and are each a hydrogen atom, a lower hydrocarbon radical or a chemical bond, Z is --O--, a group of the formula --S--(O)n-in which n is an integer of 0 to 2 or a group of the formula ##STR4## in which R.sup.3 is a hydrogen atom, a lower hydrocarbon radical optionally having substituent (s), a group attached through --CO-- or --S(O)m (m is 1 or 2) or a chemical bond, --B-- is a divalent cyclic group optionally having substituent(s) of a lower alkylene group optionally having substituent (s), --COOR.sup.6 and --COOR.sup.7 may be the same or different and are each a carboxyl group which may be esterified, and i and j are an integer of 0 to 3 provided that i+j=1 to 3, or its salt thereof, which is useful an antitumor agent, U.S. Pat. No. 4,996,206 describes a compound of the formula: ##STR5## in which R.sup.1 is --OH or --NH.sup.2 ;
R.sup.3 is 1,4-phenylene or 1,3-phenylene unsubstituted or substituted with chloro, fluoro, methyl, methoxy, or trifluoromethyl: thienediyl or furanediyl each unsubstituted or substituted with chloro, fluoro, methyl, methoxy, or trifluoromethyl: cyclohexanediyl: or alkanediyl: PA1 R.sup.4 is hydrogen, methyl, or hydroxymethyl: PA1 R.sup.5 is hydrogen or alkyl of 1 to 6 carbon atoms: PA1 R.sup.3 is thienediyl or furanediyl each unsubstituted or substituted with chloro, fluoro, methyl, methoxy, or trifluoromethyl; cyclohexanediyl; or alkanediyl; PA1 R.sup.4 is hydrogen, methyl, or hydroxymethyl; the configuration about the carbon atom designated * is S: and the pharmaceutically acceptable salts thereof, which is used as antineoplasmic agents. PA1 (1) compounds of the formula (I): ##STR7## wherein a ring A stands for an optionally substituted 5-membered ring; B stands for an optionally substituted divalent cyclic or chain group; either one of Q.sup.1 and Q.sup.2 stands for N and the other stands for N or CH; X stands for an amino group, hydroxyl group or mercapto group; Y stands for hydrogen atom, a halogen atom or a group bonded through carbon, nitrogen, oxygen or sulfur atom; Z stands for a straight-chain divalent group having 2 to 5 atoms constituted of optionally substituted carbon atoms or constituted of optionally substituted carbon atoms and one optionally substituted hetero atom; COOR.sup.1 and COOR.sup.2 independently stand for an optionally esterified carboxyl group; n denotes an integer of 2 to 6; and R may be different in each of n repeating units, or their salts, PA1 (2) a method of producing a compound of the formula (I) or a salt thereof, which is characterized by allowing a compound of the formula (II): ##STR8## wherein the symbols are of the same meaning as defined in the formula (I), or a reactive derivative thereof at the carboxyl group to react with a compound of the formula (III): ##STR9## wherein the symbols are of the same meaning as defined in the formula (I), and PA1 (3) an anti-tumor composition comprising a compound of the formula (I) or a salt thereof.
the configuration about the carbon atom designated * is S: and the pharmaceutically acceptable salts thereof, which is used as antineoplasmic agents, and
U.S. Pat. No. 5,028,608 describes a compound of the formula: ##STR6## in which R.sup.1 is --OH or --NH.sub.2 :
However, their compounds (A), (B), (C) and (D) having a pyrrolo[2,3-d] pyrimidine skeleton are not in the form of oligoglutamates at their side chain.
What is now specifically desired in the field of cancer therapy is the creation of drugs which have toxicities highly specific to cancer cells based on the action mechanism having excellent therapeutic effects. The MTX whose principal action mechanism consists in inhibition of dihydrofolate reductase is clinically used widely, though the therapeutic effect is still unsatisfactory because is has relatively strong toxicity with little effect on solid cancer.